US9205147B2 - Composition comprising iscom particles and live micro-organisms - Google Patents
Composition comprising iscom particles and live micro-organisms Download PDFInfo
- Publication number
- US9205147B2 US9205147B2 US14/146,365 US201414146365A US9205147B2 US 9205147 B2 US9205147 B2 US 9205147B2 US 201414146365 A US201414146365 A US 201414146365A US 9205147 B2 US9205147 B2 US 9205147B2
- Authority
- US
- United States
- Prior art keywords
- iscom
- virus
- vaccine
- ferret
- live
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 88
- 244000005700 microbiome Species 0.000 title claims abstract description 67
- 239000002245 particle Substances 0.000 title claims abstract description 60
- 239000011159 matrix material Substances 0.000 claims description 70
- 241000700605 Viruses Species 0.000 claims description 62
- 239000000427 antigen Substances 0.000 claims description 58
- 102000036639 antigens Human genes 0.000 claims description 58
- 108091007433 antigens Proteins 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 22
- 150000002632 lipids Chemical class 0.000 claims description 18
- 235000009001 Quillaja saponaria Nutrition 0.000 claims description 16
- 150000002338 glycosides Chemical class 0.000 claims description 15
- 241001454523 Quillaja saponaria Species 0.000 claims description 14
- 230000005847 immunogenicity Effects 0.000 claims description 14
- 241001092142 Molina Species 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 11
- 229930182470 glycoside Natural products 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- UZQJVUCHXGYFLQ-AYDHOLPZSA-N [(2s,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-4-[(2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-6-(hydroxymethyl)-4-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-3,5-dihydroxy-6-(hy Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)CC(O)[C@]1(CCC(CC14)(C)C)C(=O)O[C@H]1[C@@H]([C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O[C@H]4[C@@H]([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)[C@H](O)[C@@H](CO)O4)O)[C@H](O)[C@@H](CO)O3)O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UZQJVUCHXGYFLQ-AYDHOLPZSA-N 0.000 claims description 8
- 210000003918 fraction a Anatomy 0.000 claims description 8
- 210000000540 fraction c Anatomy 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 abstract description 55
- 230000000890 antigenic effect Effects 0.000 abstract description 27
- 229960005486 vaccine Drugs 0.000 description 120
- 241000282341 Mustela putorius furo Species 0.000 description 91
- 238000009472 formulation Methods 0.000 description 31
- 230000000694 effects Effects 0.000 description 16
- 241000712083 Canine morbillivirus Species 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 13
- 150000007949 saponins Chemical class 0.000 description 13
- 241000282339 Mustela Species 0.000 description 12
- 229930182490 saponin Natural products 0.000 description 12
- 235000017709 saponins Nutrition 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 230000003362 replicative effect Effects 0.000 description 11
- 241000711895 Bovine orthopneumovirus Species 0.000 description 10
- 206010037742 Rabies Diseases 0.000 description 10
- 230000002238 attenuated effect Effects 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 9
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 238000004113 cell culture Methods 0.000 description 9
- 238000010790 dilution Methods 0.000 description 9
- 239000012895 dilution Substances 0.000 description 9
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 9
- 241000712461 unidentified influenza virus Species 0.000 description 9
- 241000282472 Canis lupus familiaris Species 0.000 description 8
- 238000002965 ELISA Methods 0.000 description 8
- 241000711798 Rabies lyssavirus Species 0.000 description 8
- UMWKZHPREXJQGR-UHFFFAOYSA-N n-methyl-n-(2,3,4,5,6-pentahydroxyhexyl)decanamide Chemical compound CCCCCCCCCC(=O)N(C)CC(O)C(O)C(O)C(O)CO UMWKZHPREXJQGR-UHFFFAOYSA-N 0.000 description 8
- 239000011550 stock solution Substances 0.000 description 8
- 241000701931 Canine parvovirus Species 0.000 description 7
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000013598 vector Substances 0.000 description 7
- 241000287828 Gallus gallus Species 0.000 description 6
- 229940124861 Rabies virus vaccine Drugs 0.000 description 6
- 210000002257 embryonic structure Anatomy 0.000 description 6
- 238000002255 vaccination Methods 0.000 description 6
- 241000282326 Felis catus Species 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 208000035473 Communicable disease Diseases 0.000 description 4
- 241000282324 Felis Species 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 229940124590 live attenuated vaccine Drugs 0.000 description 4
- 229940023012 live-attenuated vaccine Drugs 0.000 description 4
- LVTJOONKWUXEFR-UEZXSUPNSA-N protodioscin Chemical compound O([C@@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@H](O)[C@@H](O)[C@H](C)O1)O)O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@@H]5O[C@]([C@H]([C@@H]5[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1)C)(O)CC[C@@H](C)CO[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O LVTJOONKWUXEFR-UEZXSUPNSA-N 0.000 description 4
- QDQWGYLCDZBAMD-UHFFFAOYSA-N saponin C Natural products CC1C2C3CCC4C5(C)CCC(O)C(C)(COC6OC(CO)C(O)C(O)C6O)C5CCC4(C)C3(C)CCC27C8OC8C1(C)OC7=O QDQWGYLCDZBAMD-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- 210000000605 viral structure Anatomy 0.000 description 4
- PIGTXFOGKFOFTO-FVFWYJKVSA-N (2S,3S,4S,5R,6R)-6-[[(3S,4S,4aR,6aR,6bS,8R,8aR,12aS,14aR,14bR)-8a-carboxy-4-formyl-8-hydroxy-4,6a,6b,11,11,14b-hexamethyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound O([C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)C[C@@H](O)[C@]1(CCC(C[C@H]14)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O PIGTXFOGKFOFTO-FVFWYJKVSA-N 0.000 description 3
- SMRPGWBDLOQHOS-UHFFFAOYSA-N 5-[4,5-dihydroxy-6-(hydroxymethyl)-3-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxy-3,4-dihydroxy-6-[[9-hydroxy-4-(hydroxymethyl)-4,6a,6b,8a,11,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]oxane-2-carboxylic acid Chemical compound OC1C(O)C(O)C(C)OC1OC1C(OC2C(OC(C(O)C2O)C(O)=O)OC2C(C3C(C4C(C5(CCC6(C)C(O)CC(C)(C)CC6C5=CC4=O)C)(C)CC3)(C)CC2)(C)CO)OC(CO)C(O)C1O SMRPGWBDLOQHOS-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 241000701157 Canine mastadenovirus A Species 0.000 description 3
- 241000714165 Feline leukemia virus Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940023860 canarypox virus HIV vaccine Drugs 0.000 description 3
- 230000000120 cytopathologic effect Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 235000013601 eggs Nutrition 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002519 immonomodulatory effect Effects 0.000 description 3
- 230000002458 infectious effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 210000001161 mammalian embryo Anatomy 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 229960003127 rabies vaccine Drugs 0.000 description 3
- PPRSVUXPYPBULA-UHFFFAOYSA-N saponin A Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(OC6OC(CO)C(O)C(O)C6=O)C(C)(C)C5CCC34C)C2C1)C(=O)O PPRSVUXPYPBULA-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000588779 Bordetella bronchiseptica Species 0.000 description 2
- 241001647378 Chlamydia psittaci Species 0.000 description 2
- 208000000655 Distemper Diseases 0.000 description 2
- 101800001467 Envelope glycoprotein E2 Proteins 0.000 description 2
- 241000701087 Felid alphaherpesvirus 1 Species 0.000 description 2
- 241000714201 Feline calicivirus Species 0.000 description 2
- 108010015899 Glycopeptides Proteins 0.000 description 2
- 102000002068 Glycopeptides Human genes 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 108010028921 Lipopeptides Proteins 0.000 description 2
- 201000005505 Measles Diseases 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 208000005647 Mumps Diseases 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- 241001092473 Quillaja Species 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- 102400000368 Surface protein Human genes 0.000 description 2
- 101800001271 Surface protein Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 229960001212 bacterial vaccine Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 208000014058 canine distemper Diseases 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229910001679 gibbsite Inorganic materials 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000008131 glucosides Chemical class 0.000 description 2
- 230000035931 haemagglutination Effects 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 208000010805 mumps infectious disease Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229960003131 rubella vaccine Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000003501 vero cell Anatomy 0.000 description 2
- 229960004854 viral vaccine Drugs 0.000 description 2
- 230000005727 virus proliferation Effects 0.000 description 2
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000701083 Bovine alphaherpesvirus 1 Species 0.000 description 1
- 208000010884 Bursa disease Diseases 0.000 description 1
- 241000178270 Canarypox virus Species 0.000 description 1
- 241001353878 Canine parainfluenza virus Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000002613 Feline Panleukopenia Diseases 0.000 description 1
- 241000701915 Feline panleukopenia virus Species 0.000 description 1
- 241000701925 Feline parvovirus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 229940124841 Herpesvirus vaccine Drugs 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 241001500351 Influenzavirus A Species 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 241001550390 Leptospira interrogans serovar Canicola Species 0.000 description 1
- 206010024238 Leptospirosis Diseases 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000006758 Marek Disease Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 description 1
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 206010040550 Shigella infections Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 201000005010 Streptococcus pneumonia Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 208000004006 Tick-borne encephalitis Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940031567 attenuated vaccine Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- -1 carrier Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 229940032077 cervical cancer vaccine Drugs 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 229940031670 conjugate vaccine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 231100000249 enterotoxic Toxicity 0.000 description 1
- 230000002242 enterotoxic effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 108010043839 feline leukemia virus vaccine Proteins 0.000 description 1
- QPJBWNIQKHGLAU-IQZHVAEDSA-N ganglioside GM1 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@H](NC(=O)CCCCCCCCCCCCCCCCC)[C@H](O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 QPJBWNIQKHGLAU-IQZHVAEDSA-N 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000002766 immunoenhancing effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 229940031551 inactivated vaccine Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229940041323 measles vaccine Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940095293 mumps vaccine Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940031418 trivalent vaccine Drugs 0.000 description 1
- 229960002109 tuberculosis vaccine Drugs 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 239000010913 used oil Substances 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 229940021648 varicella vaccine Drugs 0.000 description 1
- 229940126580 vector vaccine Drugs 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
- 229960001515 yellow fever vaccine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
- A61K2039/5252—Virus inactivated (killed)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/70—Multivalent vaccine
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18611—Respirovirus, e.g. Bovine, human parainfluenza 1,3
- C12N2760/18634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- the present invention relates to the use of iscom particles as adjuvant for preparing of an antigenic composition, which comprises live micro-organisms and a composition comprising at least one iscom particle and one or more living micro-organisms.
- Today adjuvants are used to enhance the immunogenicity of antigens which are not replicating i.e. in so-called killed or inactivated vaccines. Although, many vaccines contain several kinds of vaccine antigens in order to cover immune protection against several infectious diseases live and killed vaccine antigens are not mixed. One reason for that is that killed vaccines need adjuvant to enhance the efficacy of killed vaccines.
- Live vaccines contain micro-organisms that replicate in the host i.e. the live attenuated vaccine antigens which are micro-organisms that are closely related to the pathogen i.e. the micro-organisms that cause disease.
- the host is producing most of the vaccine antigens when replicating vaccine antigens are used resulting in in vivo production of high doses of vaccine antigens in the host.
- a frequently used killed vaccine for dog and cat is the rabies virus vaccine.
- Bordetella bronchiseptica (Bb) is also desired as a killed vaccine, since the live vaccine causes side effects.
- a killed Bb component vaccine (sub unit) would need adjuvant supplementation.
- These vaccines are single component vaccines.
- the killed Rabies virus vaccine requires adjuvant, and so far aluminium hydroxide is used, which adsorbs the micro-organisms and interferes thereby with their replication.
- the feline leukemia virus is a killed vaccine (sub unit) based on gp70, being a surface protein of the virus. Also this vaccine antigen requires adjuvant.
- the present used adjuvant formulation is composed of free saponin (QS21) and Al(OH)3, a mixture that will lyse viral membranes and kill the virus.
- the AI(OH)3 component causes in rare cases fibrosarcoma, conceived to be caused by the depot effects of some adjuvants e.g., oil or Al(OH)3 (report from the Veterinary Products Committee Working Group on Feline and Canine Vaccination Department for Environment, Food & Rural Affairs (DEFRA) Publications Admail 6000 London SWIA2XX).
- iscoms and iscom matrix particles can be used as adjuvants for killed vaccine antigens e.g. in a multi component vaccine without causing negative effects on the live replicating vaccine components. This is contrary to most (other) commonly used adjuvants that decrease the capacity of the live microorganisms to replicate.
- the iscom/iscom-matrix adjuvant was not only harmless to the live components, it also enhanced the immune response against the live vaccine components.
- the present invention relates to the use of iscom particle(s) as adjuvant in a formulation of vaccine antigens, which comprise at least one iscom—iscom matrix particle together with a non-replicating vaccine antigen and one or more living micro-organisms.
- the present invention relates to the use of an iscom or iscom matrix particle as adjuvant together with one or more non-replicating i.e. killed vaccine antigen(s) in an antigenic composition, which comprises at least one type of live micro-organism.
- the killed vaccine antigen may also include virus and bacteria (vectors) that contain foreign antigen(s) of interest for prophylaxes and therapy expressed by inserted genes in the vector.
- live micro-organism we understand a micro-organism that can replicate in the host.
- the live micro-organism must not be in a condition to cause adverse reactions in the host. Therefore, preferably attenuated micro-organisms are used. Attenuation is known in the art and may be performed as described in New Vaccine Technologies (2001) Ed. Ronald W Ellis, Austin, Tex., USA.
- the live i.e. replicating micro-organism may be any micro-organism of interest for use as an antigen for triggering or modulating the immune system. It also includes virus and bacteria (vectors) that contain foreign antigen(s) of interest for prophylaxes and therapy expressed by inserted genes in the vector.
- the micro-organisms may be chosen from viruses including smallpox virus, Japanese encephalitis virus, yellow fever vaccines, poliovirus vaccines, measles vaccines, rubella vaccines, mumps vaccines and trivalent vaccines including measles, mumps-rubella vaccines or even one more live virus vaccine i.e.
- varicella vaccine gram+ and gram ⁇ live bacterial vaccines including live attenuated mycobacterium bovis (BCG Tuberculosis Vaccine), live attenuated Salmonella typhi , live attenuated Shigella spp, live virulence-attenuated vibrio cholerae, pediatric.
- An example of an adeno vector is a vaccine expressing a tumor antigen p53 registered for therapy of head and neck squamous carcinoma. In clinical trials is a cervical cancer vaccine where the antigen is expressed by a vaccinia virus (modified vaccinia Ankara /MVA/) (Nature Biotechnology Vol 22 No 1 January 2004).
- live vaccines in animals are vaccines against Canine distemper virus, Canine parvovirus, Canine adenovirus, Bordetella bronchiseptica virus, Parainfluenza 3 viruses in dogs and cattle, Feline parvovirus such as Feline panleukopenia virus, Feline calici virus, Feline herpesvirus and Feline Chlamydia psittaci virus.
- replicating vector vaccine for cat is feline leukemia virus vaccine, in which the surface protein gp70 of the virus is expressed by a canarypox virus (ALVAC) and the poultry vaccines against Marek's disease where the vaccine antigen is expressed by the ALVAC vector and the vaccine against infectious bursa disease virus for which also the ALVAC vector is used.
- ALVAC canarypox virus
- One purpose of the invention is to raise the vaccine effect of live, preferably attenuated micro-organisms.
- another purpose of the invention is to provide a composition where live possibly attenuated micro-organisms are mixed with killed micro-organisms and an adjuvant.
- the iscom particles may also be used in a composition that further comprises at least one killed or inactivated micro-organism together with one or more live microorganisms.
- Inactivation is known in the art and may be performed as described in New Vaccine Technologies (2001) Ed. Ronald W Ellis, Austin, Tex., USA or as described by Rueda. P. et al. 2001. Vaccine 19 (2001) p. 726-734. Effect of different baculovirus inactivation procedures on the integrity and immunogenicity of Porcine Parvo virus-like particles.
- Different species of micro-organisms may be used in the same composition comprising the iscom particles or in different compositions for co-administration at the same event.
- the invention also relates to the use of the iscom particles together with live microorganisms in a vaccine composition for eliciting an immune protection in a host treated with the vaccine.
- Live attenuated vaccines are sometimes overattenuated and thus poorly immunogenic and it is of great interest to improve the immunogenicity also of the live vaccine components.
- Inactivated bacterial vaccines that include conjugate or sub-unit vaccines such as group Streptococci , group A Streptococci, Haemophilus influenzae, Neisseria meningitides, Bordetella pertussis, Streptococcus pneumonia, Mycoplasma pneumonia .
- conjugate or sub-unit vaccines such as group Streptococci , group A Streptococci, Haemophilus influenzae, Neisseria meningitides, Bordetella pertussis, Streptococcus pneumonia, Mycoplasma pneumonia .
- adult attenuated vaccines are those against cholera, enterotoxic E. coli, shigellosis , etc.
- Killed vaccines are, for use in animals (dogs) parvovirus vaccine, rabies virus vaccines, vaccines against leptospirosis such as Leptospira canicola, Leptospira icterohaemorrhagiae and vaccine against respiratory syncytial and bovine virus diarrhoea virus, bovine herpes virus 1 in cattle, or influenza viruses in horse.
- animals dogs
- rabies virus vaccines vaccines against leptospirosis such as Leptospira canicola, Leptospira icterohaemorrhagiae and vaccine against respiratory syncytial and bovine virus diarrhoea virus, bovine herpes virus 1 in cattle, or influenza viruses in horse.
- Feline panleukopenia (parvo) virus vaccine Feline calici virus vaccine
- Feline herpesvirus vaccine Feline Chlamydia psittaci vaccine
- Feline leukemia virus (FeLV) vaccine Fe
- killed vaccines for use in humans are inactivated virus vaccines include tick-borne encephalitis-, rabies-, hepatitis A-, polio-, influenza viruses.
- the invention may be used with any killed or live preferably attenuated micro-organism for any species and the above mentioned examples do not limit the scope of the invention.
- the invention also relates to the use of iscom particles whereby the antigenic composition further comprises one or more antigenic molecules.
- the iscom particle may be an iscom or an iscom matrix particle or any sub-fragment thereof.
- Iscom contains at least one glycoside, at least one lipid, and at least one kind of antigen substance or epitope. These substances may be of different kind such as proteins and peptides, glycoproteins and glycopeptides, carbohydrates etc. These complexes enhance the immunogenicity of the included antigens and may also contain one or more immunomodulatory (adjuvant-active) substances. Iscoms may be prepared as described in EP 0 109 942 BI, EP 0 242 380 BI and EP 0 180 546 B1.
- Matrix contains at least one glycoside, which is an adjuvant-active substance and at least one lipid. Matrix has an immunoenhancing effect on co-administered antigenic substances, see EP 0 436 620 B1. Matrix may contain other immunostimulating and enhancing components than saponins e g lipopolysaccharides (LPS), Lipid A or Lipid A derivatives, CT or LT and their sub-fragments or derivatives thereof e.g., LTB, LTA, CTB, CTA or CTAT-DD.
- LPS lipopolysaccharides
- Iscom particles containing such antigenic molecules integrated into the particle, coupled on to the particle or simply mixed into the composition may be used together with the live and/or inactivated micro-organisms.
- the lipids used are particularly those described in the applicant's patent EP 0 109 942 B1 in particular on p. 3 and in patent EP 0 436 620 B1 on p. 7 lines 7-24.
- sterols such as cholesterol and phospholipids such as phosphatidylethanolamine and phosphatidylcholine are used.
- Lipid-containing receptors that bind to the cell-binding components such as glycolipids including the cholera toxin's receptor, which is the ganglioside GM1, and fucosed blood group antigen may be used.
- the cell-binding components can then function as mucus targeting molecule and be bound to the lipid-containing substances through simply mixing them with complexes that contain them. Iscom complexes comprising such receptors and receptors are described in WO 97/30728.
- the glycoside in the iscom particles may be any glucoside.
- Preferred glucosides are described in EP 0 109 924 B1.
- raw extract from Quillaja Saponaria Molina (Dalsgaard, K. (1974), Arch. Automate Virusforsch, 44, 243.), or any subfraction thereof as described in PCT/US/88101842 to Kensil et al., Kensil, C. A. et al. (1991), J. Immunol., 146, 431, Kersten, G. F. A. et al. (1990). “Aspects of Iscoms. Analytical, Pharmaceutical and Adjuvant Properties; Thesis, University of Utrecht, EP 0 362 279 B2 and EP 0 555 276 B1.
- the saponin fractions according to the invention may be the A, B and C fractions described in WO 96/11711, the B3, B4 and B4b fractions described in EP 0 436 620, and the fractions QA1-22 described in EP 0 362 279 B2, Q-VAC (Nor-Feed, AS Denmark), Quillaja Saponaria Molina Spikoside (Isconova AB, Uppsala Science Park, 751 83, Uppsala, Sweden).
- Preferably sub fractions A and C are used. It has surprisingly turned out that A-matrix and C-matrix enhances virus growth (see Example 2).
- one saponin fraction from Quillaja Saponaria Molina is used throughout this specification and in the claims as a generic description of a semi-purified or defined saponin fraction of Quillaja Saponaria or a substantially pure fraction. It is important that the fraction does not contain as much of any other fraction to negatively affect the good results that are obtained when the mixtures of iscom or iscom matrix comprising essentially one fraction is used.
- the saponin preparation may, if desired, include minor amounts for example up to 40% by weight, such as up to 30% by weight, up to 25% by weight, up to 20% by weight, up to 15% by weight, up to 10% by weight, up to 7% by weight, up to 5% by weight, up to 2% by weight, up to 1% by weight, up to 0.5% by weight, up to 0.1% by weight of other compounds such as other saponins or other adjuvant materials.
- the antigenic molecules may be coupled on to the iscom matrix particle or simply mixed into the composition and used together with the live and/or inactivated micro-organisms.
- the antigenic molecules which may be incorporated into or associated with the iscom matrix in accordance with this invention may be any chemical entity which can induce an immune response in an individual such as (but not limited to) a human or other animal, including but not limited to a humoral and/or cell-mediated immune response to bacteria, viruses, mycoplasma or other micro-organisms.
- the specific immunogen can be a protein or peptide, a carbohydrate, polysaccharide, a lipopolysaccharide or a lipopeptide; or it can be a combination of any of these.
- the specific antigenic molecule can include a native protein or protein fragment, or a synthetic protein or protein fragment or peptide; it can include glycoprotein, glycopeptide, lipoprotein, lipopeptide, nucleoprotein, nucleopeptide; it can include a peptide-peptide conjugate; it can include a recombinant nucleic acid expression product.
- immunogens examples include, but are not limited to, those that are capable of eliciting an immune response against viral or bacterial hepatitis, influenza, diphtheria, tetanus, pertussis, measles, mumps, rubella, polio, pneumococcus, herpes, respiratory syncytial virus, haemophilus influenza, chlamydia, varicella-zoster virus, rabies or human immunodeficiency virus.
- iscom particle Any type of iscom particle, iscom matrix particle, live and inactivated micro-organism and antigenic substance may be used together in a composition for use as an antigenic or immune modulating agent according to the invention.
- one or more iscom particles, iscom matrix particles, live and inactivated micro-organisms and antigenic substances may be used together in a composition for use as an antigenic or immune modulating agent according to the invention.
- the invention also concerns a composition
- a composition comprising at least one iscom particle and one or more living micro-organisms.
- the composition may be a vaccine, wherein the living micro-organism is a virus.
- Such a composition may further comprise one or more killed or inactivated micro-organisms. It may also comprise one or more antigenic molecules.
- composition may be used for animals within the veterinary medicine and for humans.
- compositions according to the present invention may include, in addition to active ingredient, a pharmaceutically acceptable excipient, diluent, carrier, buffer, stabilizer, additive or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration.
- a live vaccine antigen is generally freeze dried and before administration the vaccine antigens (live micro-organisms) are dissolved in a pharmaceutically acceptable solvent.
- the solubilized, or suspended vaccine antigens shall immediately be administered to the individual.
- the freeze dried antigen is dissolved/suspended in a solvent that may contain the adjuvant i.e. iscom matrix or iscom formulation with or without the killed vaccine and/or antigenic substance(s).
- the solvent is mixed with the iscom matrix and/or iscom particles and/or the killed micro-organisms and/or the antigenic molecules.
- the pharmaceutically acceptable solvent may be a buffer e.g. PBS.
- the live micro-organisms are preferably supplied freeze dried separate from the adjuvant particles.
- the invention also relates to a kit of parts comprising at least one compartment containing at least one living organism and at least one compartment containing at least one iscom particle.
- a kit of parts may comprise different compartments e.g. one or more compartments comprising at least one freeze dried live micro-organism and at least one compartment comprising at least one iscom particle.
- the iscom particle is preferably dissolved or suspended in a pharmaceutical acceptable solvent.
- kits of parts which further comprises also at least one inactivated micro-organism, which may be present in a further compartment or in the same compartment as one compartment containing at least one iscom particle.
- antigenic molecules When antigenic molecules are present they may be integrated into or coupled on to an iscom particle or mixed with one or more iscom matrix particles and kept in the same compartment.
- the amount of antigenic substance, inactivated micro-organism and live micro-organism is dependent on the substance and micro-organisms used and the individual to be treated.
- the content of live micro-organism further depends on the constitution of the micro-organism.
- the low dose is 0.1 ⁇ g up to 100 ⁇ g
- the low dose range from 10 ⁇ g up to 300 ⁇ g that said not to be limiting borders. In humans the dose ranges are 1 ⁇ g up to 200 ⁇ g not being the limiting border.
- ISCOMs and Iscom-Matrix are used as vaccine adjuvant antigen delivery and adjuvant systems. Their capacity to enhance the immunogenicity of selected vaccine antigens are explored in the following experiments in formulations containing both killed vaccine antigens (non-replicating) and live vaccine antigens i.e. replicating. Useful formulations must both enhance the immunogenicity of the killed vaccine antigen and be compatible with the live vaccine antigen e. they must not reduce the replication and the immunogenicity of the live vaccine antigens. It would be beneficial if the ISCOMs and Iscom-Matrix also enhance the immunogenicity of the live vaccine antigens.
- Iscom-Matrix and ISCOMs were prepared as described in EP 0 109 942 BI, EP 0 242 380 B1, EP 0 180 546 B1 and EP 0 436 620 B1. A more detailed description of the specific examples in the present application is given below.
- Phosphatidyl choline egg derived
- Lipoid E-PC Germany
- PBS (10 mM phosphate buffered 150 mM saline, pH 6.8-7.4)
- BRSV Purified bovine Respiratory syncytial virus
- a 20% (w/w) stock solution was prepared by dissolving 2.0 g dry solid MEGA-10 in 8 ml distilled water, under gentle heating (30-50° C.). The solution was filtered through 0.22 ⁇ m sterile filter, divided in aliquots and stored at ⁇ 20° C. until use.
- a 20% (w/w) stock solution was prepared by dissolving 2.0 g dry Octyl glucoside in 8 ml distilled water under gentle heating (30-50° C.). The solution was filtered through 0.22 um sterile filter, divided in aliquots and stored at ⁇ 20° C. until use.
- each cholesterol and phosphatidyl choline was dissolved in 10 ml 20% MEGA-10, by gentle heating (30-60° C.) with slow stirring.
- the solution was filtered through 0.22 ⁇ l sterile filter, divided in aliquots and stored at ⁇ 20° C. until use. Before use the frozen lipid mixtures was heated to 40-50° C. until clear.
- each cholesterol and phosphatidyl choline was dissolved in 10 ml 20% Octylglucoside under gentle heating (30-60° C.) with slow stirring.
- the solution was filtered through 0.22 ⁇ m sterile filter, divided in aliquots and stored at ⁇ 20° C. until use. Before use the frozen lipid mixtures were heated to 40-50° C. until the solution was clear.
- the Iscom-Matrix preparations were produced as outlined in Table 1.
- the mixtures were prepared as follows using the MEGA-10 dissolved lipids;
- Iscom-Matrix was verified by negative staining electron microscopy and the resulting concentrations of saponin were determined by HPLC. (San Martin and Briones, Quality control of commercial quillaja ( Quillaja saponaria Molina) extracts by reverse phase HPLC. Journal of the Science of Food and Agriculture, 80:2063-2068, 2000.
- Matrix MM-703 was prepared by mixing 5.5 ml of Matrix-A with 3.0 ml of Matrix-C.
- Purified virus was (PR8 and BRSV respectively) were diluted in PBS to a concentration of 2.0 mg/ml.
- the PR8 virus was solubilized by addition of MEGA-10 to a final concentration of 2% (w/w), the mixture was incubated for 30-60 min at r.t.
- the viral core was removed from the solubilized virus suspensions by ultracentrifugation and the supernatants containing the solubilized viral envelope glycoproteins were submitted for amino acid analysis prior to further incorporation into ISCOMs.
- This example was carried out to explore the effect of various adjuvants on the replication of virus in chicken embryos.
- the negative effect can either depend on the effect of the respective adjuvants on the virus or on the cells being the target for virus infection.
- the following adjuvant formulations were tested for their effect on live virus to explore if they would interfere with live virus antigen replication in the chicken embryo: A-matrix, C-matrix, 703-matrix, (MB703) crude Spikoside matrix, oil adjuvant (Freund's incomplete Adjuvant, aluminium hydroxide (Allhydrogel, Superfos AS), influenza virus iscoms and bovine respiratory syncytial virus iscoms.
- the Iscom and Iscom-Matrix preparations were prepared as described in EXAMPLE 1.
- a dilution in PBS 10 log 6 was prepared as working dilution.
- 100 and 200 ⁇ g of each of the adjuvant formulations were added.
- the virus—adjuvant mixtures were incubated for at least 2 hrs at r.t. before 100 ⁇ l were injected into the allantoic fluid of 11 days embryonated hens eggs.
- the allantoic fluid was harvested at day 18 of hatch.
- the level of virus replication was measured as embryo infectious dose 50 (EID50) i.e. the end point where 50% of the embryos are infected.
- EID50 embryo infectious dose 50
- the detection of infection i.e. the presence virus in the allantoic fluid from the embryonated egg, is based on the phenomenon that the influenza virus aggregates chicken red blood cells so-called hemagglutination (HA).
- the indicator virus was canine distemper virus (CDV) in VERO cell cultures tested against A-matrix, C-matrix, 703 matrix (MB703), Spikoside matrix, Q-VAC matrix, oil adjuvant, aluminium hydroxide, free saponin A, free saponin C, free 703 and free spikoside, influenza virus iscoms and bovine respiratory syncytial virus iscoms.
- CDV canine distemper virus
- VERO cell cultures tested against A-matrix, C-matrix, 703 matrix (MB703), Spikoside matrix, Q-VAC matrix, oil adjuvant, aluminium hydroxide, free saponin A, free saponin C, free 703 and free spikoside, influenza virus iscoms and bovine respiratory syncytial virus iscoms.
- the Iscom and Iscom-Matrix preparations were prepared as described in EXAMPLE 1.
- virus-adjuvant mixtures were incubated for at least 2 hrs before 200 ⁇ l of the virus-adjuvant mixture in dilutions 10 log-1 (calculated from stock virus) to dilution 10 log-5 were allowed to adsorb for 1 to 2 hours at 37° C. to Vero cell cultures adherent to the 25 cm 2 plastic surface in Costar flasks (No. 3055, Corning Inc., Corning, N.Y. 14831, USA). Thereafter, virus suspensions respectively virus-adjuvant suspensions were removed as far as possible and cell culture medium containing 2% calf serum was added to each flask.
- the level of virus replication was measured as tissue culture infectious dose 50 (TCID50), i.e. the end point where 50% of the tissue cultures are infected.
- TCID50 tissue culture infectious dose 50
- the detection of infection i.e. the presence virus in the tissue cultures is based on the cell destruction the virus is causing i.e. cytopathic effect (CPE).
- CPE cytopathic effect
- the specificity of the reaction was confirmed by immunofluorescence or by neutralization of recovered virus from the cell cultures.
- the cultures were followed and examined for 8 days when the virus controls showed 50 to 100% CPE (cell destruction), while uninfected cultures still had confluent layers of cells.
- the virus controls included virus in the same dilutions treated in the same way as the virus-adjuvant mixtures, except that the virus suspensions were not mixed with the adjuvant formulations.
- the cell controls were uninfected cells.
- the four virus controls i.e. CDV that was not pre-incubated with any of the adjuvant formulations, titered out to 4.7 TCID50 10 LOG titres.
- A-matrix, C-matrix treated virus titered both out to 5.7 i.e. a ten fold higher titre than the virus control i.e. an unexpected increase of virus growth.
- Spikoside matrix, free saponin C, free 703 and free spikoside, oil adjuvant and aluminium hydroxide decreased more than a ten fold the virus titres compared to the virus control.
- Spikoside matrix, free saponin C, free 703 and free spikoside, oil adjuvant and aluminium hydroxide can not be used together with live vaccine antigens, because they decrease the capacity to replicate, when mixed with the live vaccine antigens ( United States Pharmacopeia and National Formulary ( USP - NF )).
- A-matrix, C-matrix treated enhanced virus growth in cell cultures an unexpected result, which can lead to increased efficacy.
- the effect of various adjuvants were tested for their effect on replication of live vaccine antigens in vitro in cell cultures and in vivo in chicken embryos.
- the immunogenicity is analyzed in an animal (ferret) model using a commercial live multi-component vaccine.
- the intention was to demonstrate that an Iscom-Matrix formulation selected to enhance a killed rabies virus vaccine antigen has no negative effect on the immunogenicity of the live vaccine antigens included in the formulation.
- the live vaccine components were selected because they are commonly included in commercial vaccines for dog.
- Ferrets were divided into three groups of 6 ferrets.
- Group 1 was vaccinated at week 0 with a commercial live vaccine (live attenuated vaccine against Canine Distemper, Adeno, Parvo and Parainfluenza virus) mixed with purified killed rabies virus component.
- a commercial live vaccine live attenuated vaccine against Canine Distemper, Adeno, Parvo and Parainfluenza virus
- the Ferrets were boosted with the killed Rabies virus component.
- Groups 2 and 3 were vaccinated at week 0 with the same commercial live vaccine (live attenuated vaccine against Canine Distemper, Adeno, Parvo and Parainfluenza virus) mixed with purified killed rabies virus component adjuvanted with either of two different Iscom-Matrix preparations i.e. MM703 and MB703 respectively (prepared as described in Example 1).
- the Ferrets were boosted with the killed Rabies virus component alone (Group 1) or the Rabies component mixed with either of the two Matrix adjuvant preparations.
- Table 2 The outline of the immunization is presented in Table 2.
- Both the vaccines (freeze-dried live vaccine antigens and freeze-dried killed Rabies_virus antigen) were reconstituted in either sterile PBS or sterile PBS supplemented with 75 ⁇ l/ml of either MM703 or MB703. Vaccines were administered subcutaneously according the manufacturer of the live vaccine. One ml vaccine was administered per dose.
- the Ferrets were bled at week 0, 2, 4, 5, 6 and 8, and the sera were tested for antibodies against the vaccine components.
- the tests used were standard indirect ELISA used for routine sero-diagnostics and specially developed blocking ELISA's to confirm the specificity of the results
- Analyses in the conventional ELISA revealed that the serum antibody responses, were higher against both live antigens and against the killed rabies virus vaccine antigen in the animals immunized with the vaccine supplemented with the MM703 and MB703 formulations than in the control group, i.e. the animals in the group that was immunized with the non-adjuvanted vaccine.
- the antigenic composition can be a vaccine including at least one live virus.
- the antigenic composition further can include at least one killed or inactivated micro-organism.
- the antigenic composition further can include one or more antigenic molecules.
- the iscom particle can be an iscom that includes at least one glycoside, at least one lipid and at least one hydrophobic protein or peptide-containing antigen.
- the iscom particle also can be an iscom-matrix that includes at least one glycoside and at least one lipid.
- the iscom particle can include at least one glycoside fragment from Quil A.
- the iscom particle also can include subfragment A and/or subfragment C of Quil A.
- compositions that includes at least one iscom particle and one or more living micro-organisms.
- the living micro-organism can be a virus.
- the composition can include one or more killed or inactivated micro-organisms.
- the composition further can include one or more antigenic molecules.
- the iscom particle can include at least one glycoside fragment from Quil A.
- the iscom particle also can include subfragment A and/or subfragment C of Quil A.
- the composition further can include a pharmaceutically acceptable carrier, diluent, excipient or additive.
- kits of parts including at least one compartment containing at least one living organism and at least one compartment containing at least one iscom particle.
- the kit of parts further can include at least one inactivated micro-organism, which may be present in a further compartment or in the same compartment as the at least one compartment containing the at least one iscom particle.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
TABLE 1 | |||
Lipid mixture | Quillaja saponin | ||
(15 mg/ml) | (Frac A and/or C) | PBS |
Preparation | Amount | Amount | Volume | ||
(MATRIX) | (mg) | Volume (μl) | (mg) | Volume (μl) | (μl) |
Matrix-A | 12 | 800 | 48* | 480 | 2.0 + 8.72 |
Matrix-C | 12 | 800 | 30** | 300 | 2.0 + 8.90 |
MB-703 | 12 | 800 | 42*** | 420 | 2.0 + 8.78 |
Spikoside- | 12 | 800 | 60S | 600 | 2.0 + 8.60 |
Matrix | |||||
Q-VAC- | 12 | 800 | 120Q | 1200 | 2.0 + 8.00 |
Matrix | |||||
*Fraction A alone | |||||
**Fraction C alone | |||||
***Fraction A + C mixture, consisting of 7 parts (mg) A + 3 parts (mg) C | |||||
SSpikoside | |||||
QQ-VAC |
TABLE 2 | ||
Group | 1st vaccination (week 0) | 2nd vaccination (week 4) |
1 | Live vaccine + Killed | Killed Rabies |
Rabies | ||
2 | Live vaccine + Killed | Killed Rabies + MM703 |
Rabies + MM703 | ||
3 | Live vaccine + Killed | Killed Rabies + MB703 |
Rabies + MB703 | ||
TABLE 3 |
Indirect ELISA analysis of serum samples from Ferrets vaccinated with a combination live viral vaccine |
and killed Rabies vaccine, with or without additional Iscom-Matrix Adjuvant. |
CAV | CAV | CAV | CAV | CAV | CAV | CDV | CDV | CDV | CDV | CDV | CDV | |
Groups | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 |
Control Group | ||||||||||||
Ferret #1 | 40 | 450 | 40 | 150 | 40 | 40 | 40 | 150 | 50 | 50 | 150 | 40 |
Ferret #2 | 40 | 100 | 50 | 150 | 40 | 40 | 40 | 150 | 50 | 40 | 150 | 40 |
Ferret #3 | 40 | 450 | 150 | 150 | 50 | 50 | 40 | 150 | 40 | 40 | 50 | 150 |
Ferret #4 | 40 | 150 | 100 | 150 | 50 | 50 | 40 | 150 | 50 | 40 | 50 | 40 |
Ferret #5 | 40 | 150 | 40 | 450 | 40 | 40 | 40 | 450 | 50 | 50 | 50 | 40 |
Ferret #6 | 40 | 150 | 50 | 50 | 50 | 40 | 40 | 450 | 150 | 40 | 50 | 100 |
MB703 | ||||||||||||
Ferret #7 | 40 | 450 | 450 | 2700 | 1350 | 1350 | 40 | 150 | 450 | 450 | 450 | 450 |
Ferret #8 | 40 | 450 | 150 | 1350 | 450 | 450 | 40 | 150 | 50 | 50 | 50 | 40 |
Ferret #9 | 40 | 450 | 1350 | 4050 | 2700 | 1350 | 40 | 450 | 450 | 450 | 450 | 150 |
Ferret #10 | 40 | 50 | 40 | 1350 | 50 | 50 | 40 | 150 | 50 | 40 | 50 | 50 |
Ferret #11 | 40 | 150 | 40 | 40 | 50 | 40 | 50 | 150 | 50 | 40 | 50 | 50 |
Ferret #12 | 40 | 450 | 1350 | 4050 | 4050 | 2700 | 40 | 450 | 450 | 450 | 450 | 450 |
MM703 | ||||||||||||
Ferret #13 | 40 | 50 | 450 | 1350 | 1350 | 150 | 40 | 150 | 150 | 50 | 150 | 50 |
Ferret #14 | 40 | 150 | 1350 | 2700 | 12150 | 2700 | 40 | 150 | 150 | 450 | 450 | 450 |
Ferret #15 | 40 | 450 | 50 | 40 | 40 | 40 | 40 | 50 | 50 | 40 | 40 | 40 |
Ferret #16 | 450 | — | — | — | — | — | 40 | — | — | — | — | — |
Ferret #17 | 40 | 50 | 1350 | 4050 | 2700 | 1350 | 40 | 450 | 450 | 450 | 150 | 150 |
Ferret #18 | 40 | 150 | 40 | 40 | 50 | 50 | 40 | 1350 | 40 | 40 | 40 | 40 |
CPV | CPV | CPV | CPV | CPV | CPV | CPI5 | CPI5 | CPI5 | CPI5 | CPI5 | CPI5 | |
Groups | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 |
Control Group | ||||||||||||
Ferret #1 | 40 | 40 | 450 | 450 | 40 | 50 | 40 | 150 | 40 | 50 | 40 | 40 |
Ferret #2 | 40 | 40 | 450 | 450 | 40 | 150 | 40 | 150 | 40 | 50 | 40 | 40 |
Ferret #3 | 40 | 150 | 300 | 450 | 50 | 40 | 40 | 150 | 40 | 50 | 40 | 40 |
Ferret #4 | 450 | 150 | 450 | 1350 | 300 | 300 | 40 | 150 | 40 | 40 | 40 | 150 |
Ferret #5 | 40 | 40 | 40 | 450 | 40 | 50 | 40 | 450 | 40 | 100 | 40 | 40 |
Ferret #6 | 40 | 100 | 40 | 450 | 40 | 40 | 40 | 450 | 40 | 50 | 40 | 40 |
MB703 | ||||||||||||
Ferret #7 | 40 | 1350 | 1350 | 4050 | 1350 | 4050 | 40 | 150 | 40 | 450 | 40 | 50 |
Ferret #8 | 150 | 1350 | 1350 | 4050 | 1350 | 1350 | 40 | 150 | 40 | 40 | 40 | 40 |
Ferret #9 | 100 | 4050 | 4050 | 12150 | 4050 | 4050 | 40 | 40 | 40 | 1350 | 150 | 50 |
Ferret #10 | 150 | 450 | 1350 | 4050 | 450 | 1350 | 40 | 150 | 40 | 40 | 40 | 40 |
Ferret #11 | 100 | 450 | 150 | 300 | 150 | 900 | 50 | 150 | 50 | 40 | 50 | 40 |
Ferret #12 | 40 | 100 | 450 | 1350 | 450 | 1350 | 40 | 150 | 40 | 2700 | 1350 | 1350 |
MM703 | ||||||||||||
Ferret #13 | 150 | 1350 | 4050 | 12150 | 12150 | 12150 | 40 | 100 | 40 | 40 | 40 | 40 |
Ferret #14 | 150 | 1350 | 12150 | 12150 | 4050 | 12150 | 150 | 150 | 50 | 1350 | 1350 | 450 |
Ferret #15 | 40 | 100 | 1350 | 4050 | 900 | 4050 | 40 | 100 | 50 | 40 | 40 | 40 |
Ferret #16 | 40 | — | — | — | — | — | 40 | — | — | — | — | — |
Ferret #17 | 100 | 100 | 450 | 4050 | 450 | 4050 | 40 | 50 | 50 | 1350 | 150 | 450 |
Ferret #18 | 40 | 450 | 1350 | 4050 | 450 | 1350 | 40 | 450 | 40 | 450 | 40 | 40 |
Rab | Rab | Rab | Rab | Rab | Rab | ||
Groups | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 | |
Control Group | |||||||
Ferret #1 | 40 | 150 | 450 | 150 | 150 | 50 | |
Ferret #2 | 40 | 150 | 450 | 40 | 50 | 40 | |
Ferret #3 | 40 | 50 | 900 | 40 | 40 | 40 | |
Ferret #4 | 40 | 50 | 900 | 40 | 40 | 40 | |
Ferret #5 | 40 | 450 | 450 | 50 | 40 | 40 | |
Ferret #6 | 40 | 150 | 450 | 50 | 50 | 40 | |
MB703 | |||||||
Ferret #7 | 40 | 1350 | 900 | 4050 | 4050 | 12150 | |
Ferret #8 | 40 | 900 | 450 | 900 | 12150 | 4050 | |
Ferret #9 | 40 | 1350 | 4050 | 4050 | 4050 | 1350 | |
Ferret #10 | 40 | 900 | 4050 | 4050 | 4050 | 1350 | |
Ferret #11 | 40 | 900 | 450 | 450 | 4050 | 4050 | |
Ferret #12 | 40 | 900 | 4050 | 12150 | 12150 | 12150 | |
MM703 | |||||||
Ferret #13 | 40 | 1350 | 450 | 4050 | 12150 | 4050 | |
Ferret #14 | 40 | 1350 | 1350 | 12150 | 12150 | 4050 | |
Ferret #15 | 40 | 1350 | 150 | 900 | 4050 | 1350 | |
Ferret #16 | 40 | — | — | — | — | — | |
Ferret #17 | 40 | 1350 | 1350 | 12150 | 12150 | 4050 | |
Ferret #18 | 40 | 900 | 900 | 12150 | 12150 | 12150 | |
1. All results are in Arbitrary Units (AU) | |||||||
2. CAV = canine adenovirus, CDV = Canine distemper virus, CPV = canine parvovirus, CPI5 = canine parainfluenzavirus 5, Rab = rabies | |||||||
3. — = no data |
TABLE 4 |
Blocking ELISA analysis of serum samples from Ferrets vaccinated with a combination live |
viral vaccine and killed Rabies vaccine, with or without additional Iscom-Matrix Adjuvant. |
Rab | Rab | Rab | Rab | Rab | Rab | CAV | CAV | CAV | CAV | CAV | CAV | |
Groups | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 |
Control Group | ||||||||||||
Ferret #1 | <3 | 27 | <3 | <3 | <3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #2 | <3 | 9 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #3 | <3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #4 | <3 | 3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #5 | <3 | 9 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #6 | <3 | 3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 |
MB703 | ||||||||||||
Ferret #7 | <3 | <3 | 9 | >81 | 9 | <3 | <3 | <3 | <3 | <3 | <3 | |
Ferret #8 | <3 | <3 | 3 | 9 | >81 | 9 | <3 | <3 | 9 | 9 | 9 | 3 |
Ferret #9 | <3 | <3 | 9 | 54 | >81 | 27 | <3 | <3 | 27 | 81 | 27 | 9 |
Ferret #10 | <3 | <3 | 3 | 9 | 27 | 27 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #11 | <3 | <3 | <3 | 9 | 9 | 27 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #12 | <3 | <3 | <3 | 81 | 81 | >=81 | <3 | <3 | <3 | <3 | <3 | <3 |
MM703 | ||||||||||||
Ferret #13 | <3 | <3 | <3 | 3 | 9 | 27 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #14 | <3 | 3 | 3 | 81 | >81 | 27 | <3 | <3 | 9 | 27 | 27 | 3 |
Ferret #15 | <3 | 9 | <3 | 3 | 9 | 27 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #16 | 3 | — | — | — | — | — | <3 | — | — | — | — | — |
Ferret #17 | 3 | <3 | 3 | 18 | >81 | >=81 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #18 | 9 | <3 | <3 | 18 | >81 | >=81 | <3 | <3 | <3 | <3 | <3 | |
CDV | CDV | CDV | CDV | CDV | CDV | CPV | CPV | CPV | CPV | CPV | CPV | |
Groups | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 | wk 0 | wk 2 | wk 4 | wk 5 | wk 6 | wk 8 |
Control Group | ||||||||||||
Ferret #1 | <3 | <3 | 3 | <3 | <3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #2 | <3 | <3 | <3 | <3 | <3 | 3 | <3 | <3 | <3 | <3 | 3 | <3 |
Ferret #3 | <3 | <3 | <3 | <3 | 3 | 3 | <3 | 9 | <3 | <3 | <3 | <3 |
Ferret #4 | <3 | <3 | 6 | <3 | 3 | 9 | <3 | <3 | 3 | <3 | <3 | <3 |
Ferret #5 | <3 | 3 | 3 | <3 | <3 | 9 | <3 | <3 | <3 | <3 | <3 | <3 |
Ferret #6 | <3 | <3 | <3, | 3 | <3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 |
MB703 | ||||||||||||
Ferret #7 | <3 | 3 | 6 | <3 | 3 | <3 | <3 | <3 | 9 | 3 | 27 | 27 |
Ferret #8 | <3 | <3 | 3 | <3 | 3 | <3 | <3 | <3 | 3 | 9 | 3 | 9 |
Ferret #9 | <3 | 3 | 6 | 6 | 6 | <3 | <3 | 9 | 54 | 3 | >81 | >81 |
Ferret #10 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | 3 | 3 | 54 |
Ferret #11 | <3 | <3 | <3 | <3 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | 3 |
Ferret #12 | <3 | 9 | 3 | <3 | 9 | 3 | <3 | <3 | <3 | <3 | <3 | 9 |
MM703 | ||||||||||||
Ferret #13 | <3 | <3 | <3 | <3 | <3 | <3 | 3 | 3 | <3 | 27 | >81 | >81 |
Ferret #14 | <3 | 3 | <3 | 3 | 9 | 9 | <3 | 3 | 9 | <3 | 9 | >81 |
Ferret #15 | <3 | <3 | <3 | 3 | <3 | 9 | <3 | 27 | <3 | <3 | 3 | 27 |
Ferret #16 | <3 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 |
Ferret #17 | <3 | 3 | 9 | 3 | <3 | <3 | <3 | <3 | <3 | <3 | <3 | 9 |
Ferret #18 | <3 | 9 | <3 | 6 | <3 | 27 | <3 | <3 | <3 | <3 | <3 | 3 |
1. All results are in Titers | ||||||||||||
2. CAV = canine adenovirus, Rab = rabies virus, CDV = canine distemper virus, CPV = canine parvovirus | ||||||||||||
3. — = not tested |
Claims (20)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/146,365 US9205147B2 (en) | 2003-03-24 | 2014-01-02 | Composition comprising iscom particles and live micro-organisms |
US14/933,722 US9901634B2 (en) | 2003-03-24 | 2015-11-05 | Compositions comprising iscom particles and live micro-organisms |
US15/876,630 US10813994B2 (en) | 2003-03-24 | 2018-01-22 | Composition comprising iscom particles and live micro-organisms |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0300795 | 2003-03-24 | ||
SE0300795-2 | 2003-03-24 | ||
SE0300795A SE0300795D0 (en) | 2003-03-24 | 2003-03-24 | Composition comprising iscom particles and live micro-organisms |
PCT/SE2004/000451 WO2004084941A1 (en) | 2003-03-24 | 2004-03-24 | Composition comprising iscom particles and live micro-organisms |
US55002607A | 2007-06-11 | 2007-06-11 | |
US12/905,418 US20110081378A1 (en) | 2003-03-24 | 2010-10-15 | Composition comprising iscom particles and live micro-organisms |
US14/146,365 US9205147B2 (en) | 2003-03-24 | 2014-01-02 | Composition comprising iscom particles and live micro-organisms |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/905,418 Continuation US20110081378A1 (en) | 2003-03-24 | 2010-10-15 | Composition comprising iscom particles and live micro-organisms |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/933,722 Continuation US9901634B2 (en) | 2003-03-24 | 2015-11-05 | Compositions comprising iscom particles and live micro-organisms |
Publications (2)
Publication Number | Publication Date |
---|---|
US20140120131A1 US20140120131A1 (en) | 2014-05-01 |
US9205147B2 true US9205147B2 (en) | 2015-12-08 |
Family
ID=20290755
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/550,026 Expired - Lifetime US7838019B2 (en) | 2003-03-24 | 2004-03-24 | Composition comprising iscom particles and live micro-organisms |
US12/905,418 Abandoned US20110081378A1 (en) | 2003-03-24 | 2010-10-15 | Composition comprising iscom particles and live micro-organisms |
US14/146,365 Expired - Lifetime US9205147B2 (en) | 2003-03-24 | 2014-01-02 | Composition comprising iscom particles and live micro-organisms |
US14/933,722 Expired - Lifetime US9901634B2 (en) | 2003-03-24 | 2015-11-05 | Compositions comprising iscom particles and live micro-organisms |
US15/876,630 Expired - Lifetime US10813994B2 (en) | 2003-03-24 | 2018-01-22 | Composition comprising iscom particles and live micro-organisms |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/550,026 Expired - Lifetime US7838019B2 (en) | 2003-03-24 | 2004-03-24 | Composition comprising iscom particles and live micro-organisms |
US12/905,418 Abandoned US20110081378A1 (en) | 2003-03-24 | 2010-10-15 | Composition comprising iscom particles and live micro-organisms |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/933,722 Expired - Lifetime US9901634B2 (en) | 2003-03-24 | 2015-11-05 | Compositions comprising iscom particles and live micro-organisms |
US15/876,630 Expired - Lifetime US10813994B2 (en) | 2003-03-24 | 2018-01-22 | Composition comprising iscom particles and live micro-organisms |
Country Status (11)
Country | Link |
---|---|
US (5) | US7838019B2 (en) |
EP (1) | EP1635867B1 (en) |
AT (1) | ATE544471T1 (en) |
AU (1) | AU2004224487B2 (en) |
BR (1) | BRPI0408587A (en) |
CA (1) | CA2519806C (en) |
ES (1) | ES2379351T3 (en) |
NZ (1) | NZ542328A (en) |
SE (1) | SE0300795D0 (en) |
WO (1) | WO2004084941A1 (en) |
ZA (1) | ZA200506988B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9901634B2 (en) | 2003-03-24 | 2018-02-27 | Novavax AB | Compositions comprising iscom particles and live micro-organisms |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1838341T3 (en) | 2005-01-20 | 2013-11-04 | Isconova Ab | VACCINE COMPOSITION comprising a FIBRONECTIN BINDING PROTEIN OR A FIBRONECTIN BINDING PEPTIDE |
US7682619B2 (en) | 2006-04-06 | 2010-03-23 | Cornell Research Foundation, Inc. | Canine influenza virus |
WO2011005183A1 (en) * | 2009-07-10 | 2011-01-13 | Isconova Ab | New composition |
GB201016471D0 (en) * | 2010-09-30 | 2010-11-17 | Isis Innovation | Viral vector immunogenic compositions |
CN105555306B (en) | 2013-09-19 | 2019-12-03 | 诺瓦瓦克斯股份有限公司 | Immunogenicity Middle East respiration syndrome coronavirus (MERS-CoV) composition and method |
EP3954700A1 (en) | 2015-07-16 | 2022-02-16 | Nuritas Limited | Anti-inflammatory peptides derived from rice proteins (oryza sativa) and uses thereof |
EP3117831A1 (en) | 2015-07-16 | 2017-01-18 | Nuritas Limited | Peptides for use in promoting transport of glucose into skeletal muscle |
EP3117830A1 (en) | 2015-07-16 | 2017-01-18 | Nuritas Limited | Antibacterial peptides, and uses thereof |
EP3118216A1 (en) | 2015-07-16 | 2017-01-18 | Nuritas Limited | Cellular growth and proliferation promoting peptides, and uses thereof |
EP3118215A1 (en) | 2015-07-16 | 2017-01-18 | Nuritas Limited | Anti-inflammatory peptides, and uses thereof |
WO2018014936A1 (en) | 2016-07-18 | 2018-01-25 | Nuritas Limited | Topical compositions |
AU2017373651B2 (en) | 2016-12-05 | 2022-03-10 | Nuritas Limited | Compositions comprising peptide wkdeagkplvk |
EP3329905A1 (en) | 2016-12-05 | 2018-06-06 | Nuritas Limited | Topical cosmetic compositions comprising an oligopeptide against anti-aging of the skin |
WO2019238962A1 (en) | 2018-06-14 | 2019-12-19 | University College Cork - National University Of Ireland, Cork | Peptide for disease treatment |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4900549A (en) * | 1986-01-14 | 1990-02-13 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzion, Volksgezondheid En Cultuur | Process for preparing immunogenic complexes and pharmaceutical composition containing these complexes |
EP0415794A1 (en) | 1989-09-01 | 1991-03-06 | Mallinckrodt Veterinary Limited | Complexes having adjuvant activity |
WO1992006710A1 (en) | 1990-10-23 | 1992-04-30 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn Volksgezondheid En Cultuur | Immunogenic complexes, in particular iscoms |
WO1996011711A1 (en) | 1994-10-12 | 1996-04-25 | Iscotec Ab | Saponin preparations and use thereof in iscoms |
US5676354A (en) | 1995-07-14 | 1997-10-14 | Fuji Photo Film Co., Ltd. | Sheet film pack |
US5679354A (en) | 1988-09-30 | 1997-10-21 | Morein; Bror | Matrix with immunomodulating activity |
US5753235A (en) | 1996-02-15 | 1998-05-19 | Heska Corporation | Recombinant canine herpesviruses |
US5925359A (en) * | 1996-10-09 | 1999-07-20 | Akzo Nobel, N.V. | European vaccine strains of the porcine reproductive and respiratory syndrome virus |
US6177081B1 (en) * | 1994-03-09 | 2001-01-23 | Pacific Biotech International, Inc. | Human and marmoset activating viruses |
US20020041895A1 (en) * | 1993-10-07 | 2002-04-11 | Unite Kingdom Defence Evaluation And Research Agency. | Liposomes containing particulate materials |
WO2004030696A2 (en) | 2002-10-02 | 2004-04-15 | Nordic Vaccine Technology A/S | Composition for vaccination |
US7838019B2 (en) | 2003-03-24 | 2010-11-23 | Isconova Ab | Composition comprising iscom particles and live micro-organisms |
-
2003
- 2003-03-24 SE SE0300795A patent/SE0300795D0/en unknown
-
2004
- 2004-03-24 ES ES04723123T patent/ES2379351T3/en not_active Expired - Lifetime
- 2004-03-24 CA CA2519806A patent/CA2519806C/en not_active Expired - Lifetime
- 2004-03-24 US US10/550,026 patent/US7838019B2/en not_active Expired - Lifetime
- 2004-03-24 AT AT04723123T patent/ATE544471T1/en active
- 2004-03-24 WO PCT/SE2004/000451 patent/WO2004084941A1/en active Application Filing
- 2004-03-24 AU AU2004224487A patent/AU2004224487B2/en not_active Expired
- 2004-03-24 EP EP04723123A patent/EP1635867B1/en not_active Revoked
- 2004-03-24 NZ NZ542328A patent/NZ542328A/en not_active IP Right Cessation
- 2004-03-24 BR BRPI0408587-6A patent/BRPI0408587A/en not_active Application Discontinuation
-
2005
- 2005-08-31 ZA ZA200506988A patent/ZA200506988B/en unknown
-
2010
- 2010-10-15 US US12/905,418 patent/US20110081378A1/en not_active Abandoned
-
2014
- 2014-01-02 US US14/146,365 patent/US9205147B2/en not_active Expired - Lifetime
-
2015
- 2015-11-05 US US14/933,722 patent/US9901634B2/en not_active Expired - Lifetime
-
2018
- 2018-01-22 US US15/876,630 patent/US10813994B2/en not_active Expired - Lifetime
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4900549A (en) * | 1986-01-14 | 1990-02-13 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzion, Volksgezondheid En Cultuur | Process for preparing immunogenic complexes and pharmaceutical composition containing these complexes |
US5679354A (en) | 1988-09-30 | 1997-10-21 | Morein; Bror | Matrix with immunomodulating activity |
EP0415794A1 (en) | 1989-09-01 | 1991-03-06 | Mallinckrodt Veterinary Limited | Complexes having adjuvant activity |
WO1992006710A1 (en) | 1990-10-23 | 1992-04-30 | De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn Volksgezondheid En Cultuur | Immunogenic complexes, in particular iscoms |
US20020041895A1 (en) * | 1993-10-07 | 2002-04-11 | Unite Kingdom Defence Evaluation And Research Agency. | Liposomes containing particulate materials |
US6177081B1 (en) * | 1994-03-09 | 2001-01-23 | Pacific Biotech International, Inc. | Human and marmoset activating viruses |
WO1996011711A1 (en) | 1994-10-12 | 1996-04-25 | Iscotec Ab | Saponin preparations and use thereof in iscoms |
US5676354A (en) | 1995-07-14 | 1997-10-14 | Fuji Photo Film Co., Ltd. | Sheet film pack |
US5753235A (en) | 1996-02-15 | 1998-05-19 | Heska Corporation | Recombinant canine herpesviruses |
US5925359A (en) * | 1996-10-09 | 1999-07-20 | Akzo Nobel, N.V. | European vaccine strains of the porcine reproductive and respiratory syndrome virus |
WO2004030696A2 (en) | 2002-10-02 | 2004-04-15 | Nordic Vaccine Technology A/S | Composition for vaccination |
US7838019B2 (en) | 2003-03-24 | 2010-11-23 | Isconova Ab | Composition comprising iscom particles and live micro-organisms |
US20110081378A1 (en) | 2003-03-24 | 2011-04-07 | Isconova Ab | Composition comprising iscom particles and live micro-organisms |
Non-Patent Citations (102)
Title |
---|
A. Eichhorn et al., "The Behavior of Bruc3-ella Abortus Vaccine in Various Excipients," American Journal of Veterinary Research, 1(1): 3-17, dated Oct. 1940. |
Albert Bendelac et al., "Adjuvants of Immunity:Harnessing Innate Immunity to Promote Adaptive Immunity," J. Exp. Med., 195(5): pp. F19-F23, dated Mar. 4, 2002. |
B.A. Vanselow et al., "A bovine ephemeral fever vaccine incorporating adjuvant Quil A: A comparative study using adjuvants Quil A, aluminium hydroxide gel and dextran sulphate," The Veterinary Record, 117: 37-43, dated Jul. 13, 1985. |
B.A.Vanselow et al. "Field trials of ephemeral fever vaccines" Veterinary Microbiology, 46: 117-130, dated Mar. 8, 1995. |
Barr, Ian G., et al., ISCOMs (immunostimulating complexes): The first decade; CSL Limited, Parkville, Victoria, Australia; Immunology and Cell Biology (Feb. 1996) vol. 74, pp. 8-25. |
BCCDC Laboratory Services; A Guide to Selection and Use of Disinfectants; BC Centre for Disease Control, 2003, pp. 1-18. |
Behboudi, S., Morein, B. and Villacres-Eriksson, M.G., "Quillaja Saponin Formulations that Stimulate Proinflammatory Cytokines Elicit a Potent Acquired Cell-Mediated Immunity," Scand J. Immunol., 50, 1999, 371-377. |
Bengt Ronnberg et al., "Adjuvant activity of non-toxic Quillaja saponaria Molina components for us in ISCOM matrix," Vaccine, 13(14): 1375-1382, dated 1995. |
Bror Morein et al. "Immunomodulation by Iscoms, Immune Stimulating Complexes," Methods, 19: 94-102, dated Aug. 33, 1999. |
Bror Morein et al., Declaration under 37 CFR 1.132 submitted in U.S. Appl. No. 10/550,026, "Composition Comprising ISCOM Particles and Live Micro-organisms," pp. 1-13, exhibit A (two pages), and exhibit B (one page), dated Apr. 11, 2009. |
Carl J. Burke et al., "Formulation, Stability, and Delivery of Live Attenuated Vaccines for Human Use," Critical Reviews in Therapeutic Drug Carrier Systems, 16(1): 1-83, dated 1999. |
Chavali S., et al., Adjuvant Effects of Orally Administered Saponins on Humoral and Cellular Immune Responses in Mice; Immunobiol., vol. 174, Mar. 2, 1987, pp. 347-359. |
Chavali S., et al., An In Vitro Study of Immunomodulatory Effects of Some Saponins; International Society for Immunopharmacology, vol. 9, No. 6, Mar. 24, 1987, Great Britain, pp. 675-683. |
Choi, et al., The level of protection against rotavirus shedding in mice following immunization with a chimeric VP6 protein is dependent on the route and the coadministered adjuvant, Vaccine 20 (Mar. 2002) 1733-1740, Elsevier Science Ltd. |
Communication pursuant to Article 94(3) EPC issued in European Patent Application No. 04 712 123.8, four pages, dated Feb. 5, 2010. |
Communication pursuant to Article 94(3) EPC issued in European Patent Application No. 04 712 123.8, four pages, dated Jun. 26, 2008. |
Communication pursuant to Article 96(2) EPC issued in European Patent Application No. 04 723 123.8, four pages, dated Jul. 26, 2007. |
Communication pursuant to Article 96(2)EPC issued in European Patent Office Application No. 04 723 123.8-2402, four pages, dated Dec. 27, 2006. |
Communication under Rule 71(3) EPC issued in European Patent Application No. 04 712 123.8, thirty-four pages, dated Sep. 16, 2011. |
Data analysis filed by patentee Isconova in Request to reject opposition against EP1635867, pp. 1-4, dated Apr. 23, 2013. |
Decision to grant a European patent pursuant to Article 97(1) EPC issued in European Patent Application No. 04 712 123.8, one page, dated Jan. 12, 2012. |
Dexiang Chen et al., "Opportunities and challenges of developing thermostable vaccines," Expert Rev. Vaccines 8(5): 547-557, dated 2009. |
F. Bozic et al., "Levamisole mucosal adjuvant activity for a live attenuated Escherichia coli oral vaccine in weaned pigs," J. Vet. Pharmacol. Therap. 26: 225-231, dated Nov. 29, 2002. |
Fohlman, Jan et al., Vaccination of Balb/c mice against enteroviral mediated myocarditis; Vaccine, vol. 8, Aug. 1990; Butterworth-Heinemann Ltd; pp. 381-384. |
Francis, George, et al., The Biological Action of Saponins in Animal Systems: A Review; British Journal of Nutrition (Dec. 2002), vol. 88, pp. 587-605; The Authors 2002. |
Gideon F.A. Kersten et al., "On the structure of immune-stimulating saponin-lipid complexes (iscoms)," Biochimica et Biophysica Acta, 1062: 165-171, dated 1991. |
Gupta et al., "Adjuvants-a balance between toxicity and adjuvanticity," Vaccine, vol. 11 No. 3, pp. 293-306 (1993). |
Harold F. Stills, Jr., 2005, "Adjuvants and Antibody Production: Dispelling the Myths Associated with Freund's complete and Other Adjuvants," ILAR Journal, vol. 46, Issue 3, pp. 280-293. |
Hu, Ke-Fei et al., Immunostimulating Complexes (ISCOMs) for Nasal Vaccination; Elsevier Science B.V. Advanced Drug Delivery Reviews 51 (2001) pp. 149-159. |
Incorporation and iscom-PubMed Results; http://www.ncbi.nlm.nih.gov/siteslentrez, Jun. 14, 2009, pp. 1-3. |
Incorporation and live iscom-PubMed Results; http://www.ncbi.nlm.nih.gov/sites/entrez; Jun. 14, 2009, pp. 1-16. |
Information regarding revocation of EP1635867, oral proceedings on Dec. 6, 2013 issued in European Patent Application No. 04 712 123.8, one page, dated Dec. 6, 2013. |
Initiative for Vaccine Research, Live Attenuated Vaccines; World Health Organization, Jun. 2009, p. 1. |
Invitation pursuant to Article 94(3) and Rule 71(1) EPC issued in European Patent Application No. 04 712 123.8, three pages, dated May 30, 2011. |
Iosef, et al., Systemic and Intenstinal Antibody Screening Cell Responses and Protection in Gnotobiotic Pigs Immunized Orally With Attenuated WA Human Rotavirus and WA 2/6-Rotavirus-Like-Particles Associated With Immunostimulating Complexes, Vaccine 20 (Mar. 2002) 1741-1753. |
Ioseph et al. (Vaccine. 2002; 20: 1741-1753). * |
ISCOM Technology Platform, Isconova, http://www.isconova/technology.aspx; dated Oct. 31, 2012. |
Iscom-PubMed Results; http://www.ncbi.nlm.nih.gov/sites/entrez, Jun. 14, 2009, pp. 1-3. |
Jack Cameron, "Anthrax: the disease in relation to vaccines," Vaccine, 2: 237, dated Dec. 1984. |
Janeway, C.A., Travers, P., Walport, M.J., and Shlomchik, M.J., Immuno Biology the Immune System in Health and Disease, Garland Publishing, New York, NY, 2001, Afterword-Evolution of the Immune System: Past, Present, and Future, by Charles A.Janeway, Jr., 597-611. |
Janeway, C.A., Travers, P., Walport, M.J., and Shlomchik, M.J., Immuno Biology the Immune System in Health and Disease, Garland Publishing, New York, NY, 2001, Chapter 14-Manipulation of the Immune Response, 553-596. |
Janeway, C.A., Travers, P., Walport, M.J., and Shlomchik, M.J., Immuno Biology the Immune System in Health and Disease, Garland Publishing, New York, NY, 2001, Chapter 1-Basic Concepts in Immunology, 1-34. |
Janeway, C.A., Travers, P., Walport, M.J., and Shlomchik, M.J., Immuno Biology the Immune System in Health and Disease, Garland Publishing, New York, NY, 2001, Chapter 2-Innate Immunity, 35-91. |
K. Dalsgaard, "Thin-layer chromatographic fingerprinting of commercially available saponins," Dansk Tidsskr., 44: 327-331, dated Jun. 16, 1970. |
Karen Burke, Glynis Dunn, Morag Ferguson, Philip D. Minor, & Jeffrey W. Alamond, "Antigen Chimaeras Ofpoliovirus as Potential New Vaccines", Nature, vol. 332, Mar. 1988. (Abastract Only), pp. 1-2. |
Karin Lovgren-Bengtsson et al., "The ISCOM Technology," Methods in Molecular Medicine, vol. 42: Vaccine Adjuvants: Preparation Methods and Research Protocols, pp. 239-258, dated Apr. 2000. |
Lipford et al., "Vaccination with immunodominant peptides encapsulated in Quil A-containing liposomes induces peptide-specific primary CD8+ cytotoxic T cells," Vaccine, vol. 12 No. 1, pp. 73-80 (Jan 1994). |
Maria S. Di Genaro et al, Apr. 2003, "Attenuated Yersinia enterocolitica Mutant Strains Exhibit Differential Virulence in Cytokine-Deficient Mice: Implications for the Development of Novel Live Carrier Vaccines," Infection and Immunity, American Society of Microbiology, vol. 71, Issue 4, pp. 1804-1812. |
Marshall, B.G., Wangoo, A., O'Gaora, P., Cook, H.T., Shaw, R.J., and Young, D.B., "Enhanced Antimycobacterial Response to Recombinant Mycobacterium bovis BCG Expressing Latency-Associated Peptide," Infection and Immunity, vol. 69, No. 11, Nov. 2001, 6676-6682. |
Max Sterne et al., "The Use of Saponin Spore Vaccine for Inoculation against Anthrax in South Africa" Onderstepoort Journal of Veterinary Science and Animal Industry. 12(2): 279-301, dated Apr. 1939. |
McNeal et al. "Stimulation of Local Immunity and Protection in Mice by Intramuscular Immunization with Triple- or Double-Layered Rotavirus Particles and QS-21" Viroloogy; 243,158-166 dated Jan. 27, 1998. |
McNeal et al. (Virology. 1998; 243: 158-166). * |
McNeal, et al., Antibody responses and protection stimulated by sequential oral-parenteral immunization of mice with rotavirus, Vaccine 17 (Feb. 1999) 639-645, Elsevier Science Ltd. |
Mooij, P., Nieuwenhuis, I.G., Knoop, C.J., Doms, R.W., Bogers, W.M.J.M., Haaft, P.J.F., Niphuis, H. Koornstra W., Bieler, K., Kostler, J., Morein, B., Cafaro, A., Ensoli, B., Wagner, R., and Heeney, J.L., "Qualitative T-Helper Responses to Multiple Viral Antigens Correlate with Vaccine-Induced Immunity to Simian/Human Immunodeficiency Virus Infection," Journal of Virology, vol. 78, No. 7, Apr. 2004, 3333-3342. |
Morein, B, et al.; Iscom, A Novel Structure for Antigenic Presentation of Membrane Proteins from Enveloped Viruses; Nature, vol. 308, No. 5958, Mar. 29, 1984; reprinted from pp. 457-460; Macmillan Journals Ltd., 1984, pp. 1-3. |
Notice of opposition to a European patent issued in European Patent Application No. 04 712 123.8, twenty-one pages, dated Nov. 8, 2012. |
P. Roy et al., "Potentiation of Immune Response of Live Lentogenic Newcastle Disease Vaccine using Adjuvant," Tropical Animal Health and Production, 30: 37-39, dated 1998. |
P.G. W. Plagemann, "Hepatitis C Virus", Jun. 4, 1991, Arch Virol, vol. 120, pp. 165-180. |
Peter C.B. Turnbull. "Anthrax vaccines: past, present and future," Vaccine, 9: 533-539, dated Aug. 1991. |
Peter Hambleton et al., "Anthrax: the disease in relation to vaccines," Vaccine, 2: p. 125 and p. 127, dated Jun. 1984. |
Pierre Tiollais, Christine Pourcel & Anne Dejean, "The Hepatitis B Virus", Oct. 10, 1985, Nature, vol. 317, pp. 489-495. |
Pyle, S.W., Morein, B., Bess, J.W., Akerblom, L., Nara, P.L., Nigida, S.M., Lerche, N.W., Robey, W.G., Fischinger, P. J., and Arthur, L.O., "Immune Response to Immunostimulatory Complexes (ISCOMS) Prepared from Human Immunodeficiency Virus Type 1 (HIV-1) or the HIV-1 External Envelope Glycoprotein (gp120)," Vaccine, vol. 7, 1989, 465-473. |
Rajput, Zahid Iqbal et al., Adjuvant Effects of Saponins on Animal Immune Responses; Journal of Zhejiang University Science B, 2007 vol. 8 (3) pp. 153-161. |
Reply to communication in European Patent Application No. 04 723 123.8, eight pages, dated Jun. 26, 2007. |
Response to communication dated Jul. 29, 2013, six pages, dated Oct. 7, 2013. |
Response to communication pursuant to Article 94(3) EPC issued in European Patent Application No. 04 712 123.8, six pages, dated Oct. 6, 2008. |
Response to Invitation pursuant to Article 94(3) and Rule 71(1) EPC issued in European Patent Application No. 04 712 123.8, ten pages, dated Jun. 16, 2011. |
Response to Official action dated Feb. 5, 2010 issued in European Patent Application No. 04 712 123.8, ten pages, dated Jul. 13, 2010. |
Response to Official action dated Jul. 26, 2007 in European Patent Application No. 04 712 123.8, six pages, dated Jan. 28, 2008. |
Response to opposition issued in European Patent Application No. 04 712 123.8, twenty-six pages, dated Apr. 23, 2013. |
Roner, Michael R., et al., Antiviral Activity Obtained from Aqueous Extracts of the Chilean Soapbark Tree (Quillaja Saponaria Molina); Journal of General Virology, Jan. 2007, vol. 88, pp. 275-285. |
Rosemary E. Smith et al, May 1999, "Immune-Stimulating Complexes Induce an IL-12 Dependent Cascade of Innate Immune Responses," The Journal of Immunology, 162, pp. 5536-5546. |
S. Rao Chavali et al., "Immunomodulator Effects of Orally-Administered Saponins and Nonspecific Resistance against Rabies Infection," Int. Archs Allergy Appl. Immun., 84: 129-134, dated 1987. |
Sai Saraswathi V. et al., "A Sin of Biotechnology, Bioterrorism- Anthrax," International Journal of PharmTech Research, 2(3): 2044-2047 dated Jul.-Sep. 2010. |
SIGMA Product Information; techserv@sial.com; Saponin From Quillaja Bark Purified; Sigma Prod. No. S4521; Case Number: 8047-15-2; Oct. 25, 1996; pp. 1-3. |
Sjolander et al. "ISCOMs: and adjuvant with multiple functions" Journal of Leukocyte Biology, 64: 713-723 dated Dec. 1998. |
Sjölander et al. (Journal of Leukocyte Biology. 1998; 64: 713-723). * |
Sjolander et al. 2001. Intranasal immunisation with influenza-ISCOM induces strong mucosal as well as systemic antibody and cytotoxic T-lymphocyte. "Vaccine" vol. 19(28-29), Jul. 16, 2001, pp. 4072-4080. |
Sjolander, A. Bengtsson, K.L., Johansson, M. and Morein, B., "Kinetics, Localization and Isotype Profile of Antibody Responses to Immune Stimulating Complexes (Iscoms) Containing Human Influenza Virus Envelope Glycoproteins," Scand. J. Immunol. 43, 1996, 164-172. |
Sjolander, A., Bengtsson, K.L., and Morein, B., "Kinetics, Localization and Cytokine Profile of T Cell Responses to Immune Stimulating Complexes (iscoms) Containing Human Influenza Virus Envelope Glycoproteins," Vaccine, vol. 15, No. 9, 1997, 1030-1038. |
Sjolander, A., Land, B.V., and Bengtsson, K.L., "Iscoms Containing Purified Quillaja Saponins Upregulate both Th1-like and Th2-like Immune Responses," Cellular Immunology, 177, 1997, 69-76. |
Smith, R.E., Donachie, A.M., and Mcl Mowat, A., "Immune Stimulating Complexes as Mucosal Vaccines," Immunology and Cell Biology, 76, 1998, 263-269. |
Soren Kamstrup et al., "Preparation and characterisation of quillaja saponin with less heterogeneity than Quil-A," Vaccine, 18: 2244-2249, dated 2000. |
Sparg, S.G., et al. Biological Activities and Distribution of Plant Saponins; Journal of Ethno-Pharmacology; www.elsevier.com/locate/jethpharm; vol. 94 (Oct. 2004), pp. 219-243. |
Statistical analysis of data from Example 4, Annex 1, submitted in Opposition against EP1635867, one page, dated Aug. 11, 2012. |
Stittelaar et al 2002, Longevity of neutralizing antibody levels in macaques vaccinated with Quil A-adjuvanted measles vaccine candidates. "Vaccine" vol. 21(3-4), Dec. 13, 2002, pp. 155-157, Available online Sep. 27, 2002. |
Submission further to written submissions dated Oct. 7, 2013, one page, dated Nov. 4, 2013. |
Submission regarding Oral Proceedings Scheduled Dec. 6, 2013 submitted in European Patent Application No. 04 712 123.8, eight pages, dated Dec. 3, 2013. |
Summons to attend oral proceedings pursuant to Rule 115(1) EPC and preliminary opinion issued in European Patent Application No. 04 712 123.8, fourteen pages, dated Jul. 29, 2013. |
Takahashi, Hidemi et al.; Induction of CD8 Cytotoxic T cells by Immunization with Purified HIV-1 Envelope Protein in ISCOMs; Nature, vol. 344, Apr. 26, 1990; pp. 873-875. |
The European Agency for the Evaluation of Medicinal Products, Human Medicines Evaluation Unit; Committee for Proprietary Medicinal Products, Note for Guidance on Pharmaceutical and Biological Aspects of Combined Vaccines; London, Jul. 23, 1998 pp. 1-14. |
The European Medicines Agency, Evaluation of Medicines for Human Use; Committee for Medicinal Products for Human Use, Guideline on Adjuvants in Vaccines for Human Use; London, Jan. 20, 2005, pp. 1-18. |
Vaccine Development Overview; http://www.brown.edu/Courses/Bio-160/Projects1999/vaccineoverview, Jun. 16, 2009; pp. 1-5. |
van Binnendijk et al, 1997. Protective immunity in Macaques vaccinated with live attenuated recombinant and subunit vaccines in the presence of passively acquired antibodies. "J. Infect Diseases" vol. 175, pp. 524-532. |
Van Rooij et al., "Analysis of protective immunity against PRV infection in pigs using attenuated and inactivated PRV vaccines," Vet. Res., 31: 135, dated 2000. |
Vancott, et al., Mice Develop Effective but Delayed Protective Immune Responses When Immunized as Neonates either Intranasally with Nonliving VP6/LT (R192G) or Orally with Live Rhesus Rotavirus Vaccine Candidates, Journal of Virology, May 2006 pp. 4949-4961, American Society for Microbiology. |
Viruses, Bacterial and Fungi, Sizes and Significance; Ion Life, http://www.ionizers.org; Jun. 16, 2009, pp. 1-4. |
Ward, et al., VP6: A Candidate Rotavirus Vaccine, The Journal of Infectious Diseases, Sep. 2010, 202 (S1): S101-S107, The Infection Diseases Society of America. |
Written submission in preparation for the oral proceedings (Rule 116 EPC) issued in European Patent Application No. 04 712 123.8, twenty-four pages, dated Oct. 7, 2013. |
www.patentstorm.us/patents/6177081/description.html; Human and Marmoset Activation Viruses-U.S. Pat. No. 6,177,081, Jun. 16, 2009, p. 1. |
Yifan Zhan et al., Aug. 1998, "Control of IL-12 and IFN-y Production in Response to Live or Dead Bacteria by TNF and Other Factors," The Journal of Immunology, 161, pp. 1447-1453. |
Yuan et al., "Protective Immunity and Antibody-Secreting Cell Responses Elicited by Combined Oral Atenuated WA Human Rotavirus and Intranasal WA 2/6-VLPS With Mutant Escherichia Coli Heat-Labile Toxin in Gnotobiotic Pigs", J. of Virology, 75(19), Oct. 2001, 9229-9238. |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9901634B2 (en) | 2003-03-24 | 2018-02-27 | Novavax AB | Compositions comprising iscom particles and live micro-organisms |
US20180369369A1 (en) * | 2003-03-24 | 2018-12-27 | Novavax AB | Composition comprising iscom particles and live micro-organisms |
US10813994B2 (en) * | 2003-03-24 | 2020-10-27 | Novavax AB | Composition comprising iscom particles and live micro-organisms |
Also Published As
Publication number | Publication date |
---|---|
ATE544471T1 (en) | 2012-02-15 |
US20110081378A1 (en) | 2011-04-07 |
US20180369369A1 (en) | 2018-12-27 |
US9901634B2 (en) | 2018-02-27 |
US7838019B2 (en) | 2010-11-23 |
CA2519806C (en) | 2012-06-19 |
US20080095795A1 (en) | 2008-04-24 |
US10813994B2 (en) | 2020-10-27 |
AU2004224487A1 (en) | 2004-10-07 |
CA2519806A1 (en) | 2004-10-07 |
ZA200506988B (en) | 2006-07-26 |
AU2004224487B2 (en) | 2009-08-06 |
WO2004084941A1 (en) | 2004-10-07 |
BRPI0408587A (en) | 2006-03-21 |
US20200323979A9 (en) | 2020-10-15 |
SE0300795D0 (en) | 2003-03-24 |
NZ542328A (en) | 2009-10-30 |
EP1635867A1 (en) | 2006-03-22 |
ES2379351T3 (en) | 2012-04-25 |
US20160114034A1 (en) | 2016-04-28 |
EP1635867B1 (en) | 2012-02-08 |
US20140120131A1 (en) | 2014-05-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10813994B2 (en) | Composition comprising iscom particles and live micro-organisms | |
US20200215189A1 (en) | Iscom preparation and use thereof | |
US20220241408A1 (en) | Quil a fraction with low toxicity and use thereof | |
KR100720213B1 (en) | Microfluidized oil-in-water emulsions and vaccine compositions | |
AU2005230708B2 (en) | Microfluidized oil-in-water emulsions and vaccine compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NOVAVAX AB, SWEDEN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MOREIN, BROR;BENGTSSON, KARIN LOVGREN;SIGNING DATES FROM 20140129 TO 20140202;REEL/FRAME:032202/0580 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 8 |